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Brain Metastasis in Renal Cell Cancer Responding to Sunitinib

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					ANTICANCER RESEARCH 27: 4255-4258 (2007)




  Brain Metastasis in Renal Cell Cancer Responding to Sunitinib
                     ANGELOS K. KOUTRAS, DIMITRIOS KRIKELIS, NATASSA ALEXANDROU,
                            IOANNIS STARAKIS and HARALABOS P. KALOFONOS

    Division of Oncology, Department of Medicine, University Hospital, Patras Medical School, Rion 26504, Greece


Abstract. Background: Sunitinib (SU011248; Sutentì) is a          excision of the lesion which was histopathologically
new small molecule that inhibits members of the split-kinase      confirmed to be a metastasis from clear cell renal cancer.
domain family of receptor tyrosine kinases (RTKs), with           Postoperatively, evaluation with CT scan did not reveal
established antitumor activity in renal cancer. In the current    residual disease in the brain. Moreover, evidence of the
report, we describe a patient with a solitary brain metastasis    disease elsewhere in the body was not apparent.
from renal cell carcinoma who achieved partial response of           Immunotherapy consisting of interferon alpha (10 mU 3 x
the cerebral lesion following treatment with sunitinib. To the    weekly) was started in March 2006. Five months later,
best of our knowledge, this is the first report of sunitinib      repetition of imaging procedures (CT scan) demonstrated
activity in brain metastases from kidney cancer. A limited        relapse of the disease in the brain, with a lesion located in the
number of publications support the hypothesis that small          right parietal-occipital lobe (maximum diameter 4 cm),
tyrosine kinase inhibitors may cross the blood-brain barrier.     together with peritumoral edema (Figure 1). Again, CT scan
Although the role of sunitinib in advanced renal carcinoma        of the abdomen and the lungs was negative for local relapse
has been evaluated through prospective trials, the efficacy of    and other metastatic sites. The lesion was considered
the drug in patients with brain metastases has not been           inoperable and the patient started (August 2006) sunitinib
explored, since patients with cerebral lesions were excluded in   monotherapy at a dose of 50 mg orally once daily for 4 weeks,
those studies. Thus, we believe that accumulating evidence        followed by 2 weeks off, in repeated 6-week cycles. The
from personal experience or limited reports could be useful.      patient also received methylprednisolone at a dose of 16 mg
Moreover, in our case, sunitinib was found to be safe, leading    daily, which was progressively decreased until discontinuation,
to considerable shrinkage of the brain metastasis without any     during the following months. At that time, the patient was in
serious adverse events or central nervous system toxicities. We   a good clinical condition (Eastern Cooperative Oncology
consider this observation to be important, given the absence      Group Performance Status=0, lactate dehydrogenase=145
of data regarding the activity of the drug in this particular     U/L, haemoglobin=10.9 g/dL, corrected calcium=9 mg/dL
clinical setting.                                                 and alkaline phosphatase=63 U/L). The treatment was
                                                                  tolerated fairly well without serious adverse events.
Case Report                                                          The patient developed grade 1 hypertension (according to
                                                                  National Cancer Institute Common Toxicity Criteria, version
A 40-year-old woman underwent nephrectomy for a                   3.0) after the first cycle of the treatment, which was
moderately differentiated, clear cell adenocarcinoma of the       successfully controlled with olmesartan. Other side-effects
left kidney in August 2004. The pathological stage of the         included anemia grade 1 and hand-foot syndrome grade 1
disease was II (T2N0M0). In February 2006, the patient            (according to the above mentioned criteria). Evaluation of
complained of numbness of the left upper limb, focal              the patient with CT scan after 2 cycles of treatment
seizures and headache. Computed tomography (CT) and               (November 2006), revealed a reduction of the metastatic
magnetic resonance imaging revealed a solitary mass in the        lesion (maximum diameter 3.2 cm), together with significant
right parietal-occipital lobe. The patient underwent surgical     resolution of the associated edema (Figure 2). Given the
                                                                  response of the disease and the lack of considerable toxicity,
                                                                  treatment was continued at the same dose. Re-evaluation of
                                                                  the patient after the completion of the fifth cycle (March
Correspondence to: H.P. Kalofonos, Division of Oncology,
                                                                  2007) demonstrated further reduction of the lesion
Department of Medicine, University Hospital, Patras Medical
School, Rion 26504, Greece. Tel: +30 2610999535, Fax: +30
                                                                  (maximum diameter 2 cm), without any signs of disease
2610994645, e-mail: kalofon@med.upatras.gr                        elsewhere (Figure 3). The patient remains on treatment
                                                                  with sunitinib at the same dosage, without clinical or
Key Words: Sunitinib, renal cell cancer, brain metastases.        radiographic evidence of disease progression.


0250-7005/2007 $2.00+.40                                                                                                      4255
                                             ANTICANCER RESEARCH 27: 4255-4258 (2007)




Figure 1. CT scan of the brain before the administration of sunitinib.   Figure 2. CT scan of the brain after 2 cycles of treatment with sunitinib.




Discussion

Sunitinib (SU011248; Sutentì) is a new, orally administered,
small molecule that inhibits members of the split-kinase
domain family of receptor tyrosine kinases (RTKs),
including the vascular endothelial growth factor receptors
(VEGFRs) types 1 and 2, platelet-derived growth factor
receptors (PDGFR-· and PDGFR-‚), the stem cell factor
receptor c-KIT, the FLT3 and RET kinases (1). Sunitinib
exhibits potent antiangiogenic and antitumor activity.
Considerable clinical activity has been demonstrated in
patients with advanced renal cell carcinoma (2-4).
   Brain metastases are not a rare occurrence in patients
with kidney cancer (5). Whole-brain radiotherapy is the
standard treatment, although generally, renal tumors are
relatively radioresistant and more aggressive approaches
such as surgery or radiosurgery are indicated only in a
subset of patients. In the current report, we describe a
patient with a solitary brain metastasis from renal cell
carcinoma who achieved partial response of the cerebral                  Figure 3. CT scan of the brain after 5 cycles of treatment with sunitinib.
lesion, following treatment with sunitinib. To the best of
our knowledge, this is the first report of sunitinib activity
in brain metastases from kidney cancer. It is noteworthy
that our patient continued to respond further, seven                       A limited number of publications support the hypothesis
months after the initiation of the treatment, as was                     that small tyrosine kinase inhibitors (TKIs) may cross the
demonstrated by CT scan in March 2007. It is also                        blood-brain barrier. Gefitinib, an oral selective epidermal
interesting that seizures or other central nervous system                growth factor receptor (EGFR) tyrosine kinase inhibitor,
(CNS) toxicities were not observed during the treatment,                 has shown activity in brain metastases from non-small cell
although prophylactic anticonvulsant therapy was not                     lung cancer (NSCLC) (6-8). Responses have also been
administered.                                                            reported with erlotinib, another EGFR tyrosine kinase


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                              Koutras et al: Sunitinib for Brain Metastases in Renal Cell Cancer


inhibitor, in patients with intracranial lesions from NSCLC      References
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   In conclusion, sunitinib was found to be effective and
safe, leading to considerable shrinkage of brain metastasis
without any serious adverse events. Our case highlights the
potential of sunitinib in patients with CNS metastases from
renal cell carcinoma. We consider this observation to be                                                   Received July 12, 2007
important, given the absence of data regarding the activity                                             Revised October 16, 2007
of the drug in this particular clinical setting.                                                       Accepted October 22, 2007




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